1. Technical Field
The invention relates to a system for synthesizing labeled compounds such as [18F] 2-fluoro-2-deoxy-D-glucose, and the like, employing various single-use integrated kits of materials, valves and vessels fitted to a fixed stationary apparatus.
2. Background
F-18 compounds, exemplified by [18F] 2-Fluoro-2-Deoxy-D-Glucose (hereinafter FDG), have become widely used in nuclear medicine for diagnostic studies using a Positron Emission Tomography (PET) body scanning technique.
Production of 18F-labeled FDG is, by now, well known. Information can be found in: 1) Fowler et al., “2-Deoxy-2-[18F]Fluoro-D-Glucose for Metabolic Studies: Current Status,” Appl. Radiat. Isotopes, vol. 37, no. 8, pp. 663–668 (1986); 2) Hamacher et al., “Efficient Stereospecific Synthesis of No-Carrier-Added 2-[18F]-Fluoro-2-Deoxy-D-Glucose Using Aminopolyether Supported Nucleophilic Substitution,” J. Nucl. Med., vol. 27, pp. 235–238 1986; 3) Coenen et al., “Recommendation for Practical Production of [2-18F]Fluoro-2-Deoxy-D-Glucose,” Appl. Radiat. Isotopes, vol. 38, no. 8, pp. 605–610 (1987) (a good review); 4) Knust et al., “Synthesis of 18F-2-deoxy-2-fluoro-D-glucose and 18F-3-deoxy-3-fluoro-D-glucose with no-carrier-added 18F-fluoride,” J. Radioanal. Nucl. Chem., vol. 132, no. 1, pp. 85–91 (1989); and 5) Hamacher et al., “Computer-aided Synthesis (CAS) of No-carrier-added 2-[18F]Fluoro-2-Deoxy-D-Glucose: An Efficient Automated System for the Aminopolyether-supported Nucleophilic Fluorination,” Appl. Radiat. Isotopes, vol. 41, no. 1, pp. 49–55 (1990). See also U.S. Pat. No. 6,567,492 to Kislelev al. (20 May 2003).
Several automatic processing systems capable of production of radiopharmaceuticals, such as 18F-labeled FDG, have also been described in: 1) U.S. Pat. No. 5,808,020 to Ferrieri et al. (15 Sep. 1998); 2) U.S. Pat. No. 6,599,484 to Zigler et al. (29 Jul. 2003); PCT pub. WO2004093652 by Buchanan et al. (2004-Nov.-04); and 3) German patent DE10320552 to Maeding et al., “Apparatus marking pharmaceutical substances with fluorine isotope, preparatory to positron-emission tomography, locates anion exchanger within measurement chamber” (2004-Nov.-25).
These can be characterized as being stationary systems that do not use any removable components, where all connections of tubes and valves are permanent and do not change in day-to-day operation. Some, such as Zigler et al., describe their systems as multi-batch capable. These have the advantage of being able to save cost by reusing components. That is accomplished by rinsing all vessels and connecting tubing with solvents between production cycles without removing them from the apparatus. It is usually referred to as a Clean-in-Place (CIP) procedure. However, due to the configuration of apparatus, it may be impossible to achieve complete cleaning and sterilization of all components. In addition, the CIP approach requires substantial downtime between processing cycles, which may even exceed the duration of the processing cycle itself. CIP procedures also require extensive validation and may not be acceptable from regulatory standpoint due to the inherent risk of cross-contamination between batches. Finally, such systems cannot be easily adapted for production of multiple different products, because all plumbing components are stationary and cannot be quickly changed in normal operating conditions.
To ameliorate the CIP problems, the following disclose use of removable kits for synthesis of 18F-labeled compounds, mainly FDG: 1) U.S. Pat. No. 5,312,592 (17 May 1994) and U.S. Pat. No. 5,415,843 (16 May 1995) to Andersson (17 May 1994); 2) U.S. Pat. No. 5,759,513 to Nakazawa et al. (2 Jun. 1998); 3) U.S. Pat. No. 5,932,178 to Yamazaki et al. (3 Aug. 1999); 4) U.S. Pat. No. 6,172,207 to Damhaut et al. (9 Jan. 2001); and 5) U.S. Pub. no. 2004/0028573 A1 by Schmitz et al. (12 Feb. 2004), corresponding to EU patent EP1343533 (2003-Sep.-17). Damhaut et al. disclose a process with a preference for a single-use kit, but the physical aspects of the kit are not well developed. The other four references disclose single-use kit apparatus. The major problem is that they are dedicated to a particular process and are not easily reconfigured. This is an issue because, to save cost, injection molded plastic manufacturing should be used where possible. However, the need for any one radiopharmaceutical may not justify the investment in an injection mold for each one.
In producing FDG and other radiopharmaceuticals, there are a number of difficulties. Radioisotopes produce radiation that can damage some construction materials limiting the selection. Of course, workers must be shielded and cannot be in the presence of the processing apparatus. Such protective shielding used for this purpose must be relatively thick; a minimum 10 cm (4 in.) of lead is typically required to adequately protect personnel. The size of this shielding and its weight depend mainly on the size and dimensions of the processing apparatus. Therefore it is important that such apparatus is made as compact as possible to minimize the cost and weight of shielding. Even after a production run, the apparatus can contain enough residues so that handling the used apparatus is dangerous. A typical decay period of 12–16 hours is needed during which time equipment cannot be accessed by hand. However, to be efficient multiple batches must be processed each day, typically as many as sixteen.
As noted, a disposable kit must not be expensive compared to the value of the final product. This means that it should be made from inexpensive parts and materials and be capable of being reconfigured for different processes. Because of the short half-life of some radioisotopes (109 min. for the 18F), these products must be produced in relatively large quantities to allow for decay during delivery to the patient from a manufacturing facility. Therefore, it is necessary to perform this process automatically using systems placed within the protective shielding without manual intervention. To increase production, it is useful if the automated systems can be quickly and safely re-loaded with materials needed for the next production run.
Because of the short radioisotope half-life, production facilities are distributed in many geographical locations. Since different skill sets are required to run a radioisotope generator and a chemical process, preparation of kits on-site requires more personnel than if kits were prepared in advance at a central location. (Central preparation should also improve quality control.) However, some chemicals have a short shelf life unless kept sealed.
Another difficulty is that the cost and weight of lead shielding makes it desirable to limit the volume taken up by processing apparatus as much as possible. Typically, sizes less than 40 cm (16 in.) deep by 40 cm (16 in.) high by 20 cm (8 in.) wide would be desirable.